DE102005060821A1 - Sulfonated phosphine ligands and methods of cross-coupling aryl and heteroaryl halides and sulfonates with amines, alcohols, and carbon nucleophiles using the ligands in conjunction with transition metal catalysts - Google Patents

Abstract

Sulfonated phosphine ligands of the structure, DOLLAR F1 catalyst systems containing these ligands, and their use in cross-coupling reactions, DOLLAR A where X¶4-7¶ for carbon, nitrogen or phosphorus, X¶1-3¶ and X¶8-10¶ independently either for carbon or the group X¶i¶R¶i¶ with i = 2, 3, 4, or 5 for nitrogen or phosphorus or two adjacent X¶i¶R¶i¶ together connected by a formal double bond together stand for O , S, NH or NR¶i¶; DOLLAR AY¶1¶ and Y¶2¶ independently of one another denote the same or different bridging, bi- or triple-bonded structural elements from the group {oxygen, sulfur, substituted nitrogen or phosphorus, optionally substituted C¶1-3¶ alkylene, vinylene, Alkylidene or silaalkylene, optionally substituted arylene or heteroarylene, carboxylate, tiocarboxylate, N-substituted carboxamide or imide, optionally substituted silane, single bond}, where the middle ring can have an aliphatic, heteroaliphatic, aromatic or heteroaromatic character; with the proviso that when Y1 is -C (CH¶3¶) ¶2¶- and R¶2¶ = R¶5¶ = sulfonate, at least one more of R¶1-3¶ and R¶4 -6¶ is not hydrogen or at least one of the groups Q¶1-4¶ is not phenyl. DOLLAR A Q¶1-4¶ independently of one another mean identical or different radicals from the group {hydrogen, methyl, linear, branched or cyclic alkyl, optionally substituted, aryl, heteroaryl, optionally ...

Description

mixed aryl or heteroaryl-substituted alkyl / arylamines and arylamines or heteroaryl-substituted alkyl / aryl ethers, especially with functional Groups in the alkyl chain are as well as unsymmetrical biryls and Heterobiaryls and functionalized alkyl, vinyl and alkynylaryls or -heteroaryle meaningful and extremely versatile Intermediates in organic synthesis. The meaning in the Modern organic synthesis is only limited by accessibility limited to these classes of compounds.

standard procedures for the preparation of mixed aryl- or heteroaryl-substituted Alkyl- / arylamines and aryl- or heteroaryl-substituted alkyl / aryl ethers is the Ullmann reaction, the reaction being very high temperatures needed completely expire. However, these usually tolerate drastic reaction conditions rarely functional groups and reactive heteroaromatics and are not or only very poorly applicable to electron-deficient aromatics and difficult to control. Modern methods of manufacture These amines use the Pd or Ni catalysis in the presence different ligands. Standard method for producing mixed asymmetric biaryl and heterobiarylene, as well as alkyl, vinyl and alkynylarylene and heteroarylene are transition metal catalyzed Coupling reactions of aryl, heteroaryl or vinyl halides and sulfonates with aromatic or heteroaromatic carbon electrophiles, in particular organoboron compounds (Suzuki-Miyaura coupling), organomagnesium compounds (Kumada-Tamao-Corriu coupling), organozinc compounds (Negishi coupling), Organostannans (Stille coupling) and Alkenes (Heck reaction) and terminal alkynes (Sonogashira and Stephens-Castro coupling). A recent development involves the use of enolates, which optionally formed in situ, as electrophiles. When Catalysts are mainly found Palladium and nickel compounds in combination with different Ligands use. The available However, ligands show different disadvantages, in particular when the economically advantageous aryl or heteroaryl chlorides to be used as a coupling partner (see below).

• • Verwendung teuerer und schwer handhabbarer (teilweise pyrophorer) Liganden z.B. P^tBu₃ (zur C-N-Kupplung siehe Hartwig et al., US6100398 , zur C-C-Kupplung Fu et al., J. Am. Chem. Soc. 2000, 122, 4020, zur C-C-Kupplung von Enolaten siehe Hartwig et al., US6072073 ), sowie aufwendige Isolierung des Produktes durch Chromatographie.
• • Verwendung von Liganden, die schwierig zu synthetisieren sind (ferrocenbasierte Liganden, Hartwig et aL., WO0211883 und US6057456 ), aufwendige Isolierung des Produktes durch Chromatographie
• • aufwendige bzw. schwierige Ligandensynthesen (Buchwald et al., WO 00/02887), aufwendige Isolierung des Produktes durch Chromatographie
• • schwierige Abtrennbarkeit von Ligand- und Katalysatorresten erfordern häufig separate Reinigungsschritte, teilweise unter Zuhilfenahme teurer Spezialreagentien (Garrett, Prasad, Adv. Synth. Catal. 2004, 346, 889), da insbesondere für Pharma-Feinchemikalien sehr niedrige Spezifikationsgrenzen einzuhalten sind (z. B. < 10 oder < 5 ppm). Zusätzlich sind die üblicherweise verwendeten Katalysatorsysteme in verschiedenen anderen Reaktionen hochaktiv, so dass auch in Folgestufen unerwünschte Nebenreaktionen katalysiert werden können. Weitere Arbeiten zur Synthese der C-N-Bindung aus Arylhalogeniden bzw. -sulfonaten unter Verwendung verschiedener Katalysatoren zeichnen sich durch folgende Nachteile aus (Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1444;, Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158; Huang, J.; Grassa, G.; Nolan, S.P. Org. Lett. 1999, 1, 1307; Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575; Stauffer, S. I.; Hauck, S. I.; Lee, S.; Stambuli, J.; Hartwig, J. F. Org. Lett. 2000, 2, 1423):
• • Die Temperaturen sind in vielen Fällen sehr hoch
• • Die Selektivitäten für die Bildung der gewünschten Aniline im Gegensatz zu den ungewünschten Arinen bzw. Diarylaminen sind oft niedriger als nötig für ein optimales synthetisches Potential.

It would therefore be highly desirable to have a process that accomplishes the cross-coupling of aromatic and heteroaromatic halides and sulfonates, especially the unreactive chlorides, with nitrogen, oxygen and carbon nucleophiles, while achieving very high yields, with low catalyst and Ligand amounts requires and in addition can be used in economically useful process, which are characterized by simple separation of ligand and catalyst from the product. The previously published synthesis methods do not solve this problem or only partially and show many disadvantages, as will be demonstrated by some examples:

• Use of expensive and difficult-to-handle (partially pyrophoric) ligands, eg P ^t Bu ₃ (for CN coupling see Hartwig et al., US6100398 , to the CC coupling Fu et al., J. Am. Chem. Soc. 2000, 122, 4020, for the CC coupling of enolates, see Hartwig et al., US6072073 ), as well as complex isolation of the product by chromatography.
• Use of ligands which are difficult to synthesize (ferrocene-based ligands, Hartwig et al., WO0211883 and US Pat US6057456 ), extensive isolation of the product by chromatography
• • elaborate or difficult ligand syntheses (Buchwald et al., WO 00/02887), complex isolation of the product by chromatography
• • Difficult separability of ligand and catalyst residues often require separate purification steps, sometimes with the help of expensive special reagents (Garrett, Prasad, Adv. Synth. Catal. 2004, 346, 889), since in particular for pharmaceutical fine chemicals very low specification limits must be observed (z. <10 or <5 ppm). In addition, the catalyst systems commonly used are highly active in various other reactions, so that even in subsequent stages unwanted side reactions can be catalyzed. Further work for the synthesis of C [BOND] N bond formation from aryl halides or sulfonates using various catalysts has the following disadvantages (Wolfe, JP, Buchwald, SLJ Org. Chem., 2000, 65, 1444, Wolfe, JP, Buchwald, SLJ 2000, 65, 1158; Huang, J .; Grassa, G .; Nolan, SP Org. Lett., 1999, 1, 1307; Hartwig, JF; Kawatsura, M.; Hauck, SI; Shaughnessy, KH; Alcazar-Roman, LMJ Org Chem 1999, 64, 5575; Stauffer, SI; Hauck, SI; Lee, S., Stambuli, J .; Hartwig, JF Org. Lett. 2000, 2, 1423):
• • The temperatures are very high in many cases
• • The selectivities for the formation of the desired anilines in contrast to the unwanted arynes or diarylamines are often lower than necessary for optimum synthetic potential.

• – geringe Aktivität bei der Umsetzung von Aryl- bzw. Heteroarylchloriden, insbesondere, wenn diese elektronenreich sind;
• – hohe Reaktionstemperaturen sind notwendig;
• – Nebenreaktionen wie z.B. Homokupplung und Deborylierung treten häufig auf.

Further methods for the synthesis of the C-C bond from aryl or heteroaryl halides and sulfonates are distinguished by the following disadvantages:

• Low activity in the reaction of aryl or heteroaryl chlorides, especially when these elek are trio-rich;
• - high reaction temperatures are necessary;
• - Side reactions such as homocoupling and deborylation occur frequently.

The present invention solves all of these problems and concerns new sulfonated phosphine ligands and their use in combination with transition metals for various Cross-coupling reactions.

und werden bei Kreuzkupplungsverfahren in Verbindung mit Übergangsmetallen, insbesondere mit Palladium oder Nickel als Katalysator, eingesetzt.The ligands of the invention have the following structure:

and are used in cross-coupling processes in connection with transition metals, in particular with palladium or nickel as catalyst.

This is
X _4-7 for carbon, nitrogen or phosphorus, X _1-3 and X _8-10 independently of one another either for carbon, or the group X _i R _i with i = 2, 3, 4 or 5 for nitrogen or phosphorus or two in each case adjacent X _i R _i linked via a formal double bond together represent O (furans), S (thiophenes), NH or NR; (Pyrroles);
the radicals R _1-6 are substituents from the group {hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 20 C atoms, in which optionally one or more hydrogen atoms are replaced by fluorine or chlorine or bromine (eg CF ₃ ), substituted cyclic or acyclic alkyl groups, hydroxy, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, pentafluorosulfuranyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, thio, alkylthio, arylthio, diarylphosphino, dialkylphosphino, Alkylarylphosphino, optionally substituted aminocarbonyl, CO ₂ ^-, alkyl- or aryloxycarbonyl, hydroxyalkyl, alkoxyalkyl, nitro, cyano, aryl or alkyl sulfone, aryl- or alkylsulfonyl} or in each case two adjacent radicals R _1-5 together are an aromatic, heteroaromatic or aliphatic fused-on ring, with the proviso that at least one of R _1-3 and R _{6 4-} ei corresponds sulfonate group.

Y ₁ and Y ₂ independently of one another denote identical or different bridging, bivalent or trivalent structural elements from the group {oxygen, sulfur, substituted nitrogen or phosphorus, optionally substituted C _1-3 -alkylene, -vinylene, -alkylidene or silaalkylene, optionally substituted Arylene or heteroarylene, carboxylate, thiocarboxylate, N-substituted carboxamide or imide, optionally substituted silane, single bond}, wherein the middle ring may have aliphatic, heteroaliphatic, aromatic or heteroaromatic character;
Q _1-4 independently of one another denote identical or different radicals from the group {hydrogen, methyl, linear, branched or cyclic alkyl, optionally substituted, aryl, heteroaryl, optionally substituted} or Q ₁ and Q ₂ or Q ₃ and Q ₄ form together a ring and represent a bridging structural element from the group {optionally substituted alkylene, branched alkylene, cyclic alkylene, optionally substituted arylene or heteroarylene} or independently of one another for one or two polycyclic radicals, such as norbornyl or adamantyl; Q _1-4 may carry one or more sulfonic acid or sulfonate groups.

typical examples for Ligands are mono- or disulfonated diphosphines based on the backbones of anthracene, acridine, 9,10-dihydroacridine, 9,19-dihydroanthracene, Xanthene, phenoxathiin, thianthrene, dibenzo-p-dioxin, phenoxazine, Phenothiazine, 5,10-dihydrophenazine, carbazole, dibenzofuran, dibenzothiophene, (10,11-dihydro-) benzoxepine and -azepin, and those derived therefrom heterocyclic analogues.

In a preferred embodiment Y _{1 is} an optionally substituted alkylene group, alkylidene, vinylidene or vinylene group and Y ₂ is O and in each case one of the radicals R ₁ -R ₃ and R ₄ -R _{6 is} a sulfonate group. In the event that Y1 is -C (CH ₃ ) ₂ - and R ₂ = R ₅ = sulfonate, either at least one further of the radicals R _1-3 and R _{4-6 is} not hydrogen or at most three of the groups Q _{1 -4} represent phenyl.

In a further likewise preferred embodiment, Y _{1 is} an optionally substituted silylene or silaalkylene group and Y ₂ = O, where in each case one of the radicals R ₁ -R ₃ and R ₄ -R _{6 is} a sulfonate group.

Also preferred are ligands in which Y _{1 is} a sulfur atom or an optionally substituted thiaalkylene group and Y ₂ = O and in each case one of the radicals R ₁ -R ₃ and R ₄ -R ₆ corresponds to a sulfonate group.

Further preferred embodiments are those in which Y ₁ denotes a single bond and Y ₂ = O and in each case one of the radicals R ₁ -R ₃ and R ₄ -R ₆ corresponds to a sulfonate group, and those in which Y _{1 represents} a substituted nitrogen atom or an N -substituted azaalkylene group and Y ₂ = O and in each case one of the radicals R ₁ -R ₃ and R ₄ -R ₆ corresponds to a sulfonate group and those abovementioned ligands in which Y ₁ is sulfur instead of oxygen.

The ligands according to the invention be in the process of cross-coupling of aromatic compounds in conjunction with a transition metal catalyst used.

sowie mindestens ein Salz, einen Komplex oder eine metallorganische Verbindung eines Metalls der Gruppe (Mn, Fe, Co, Ni, Cu, Rh, Pd, Ir, Pt), bevorzugt Palladium oder Nickel. Die Symbole R_1-6, X_1-10, Y₁₊₂ und Q_1-4 haben die vorstehend genannte Bedeutung.The invention therefore further relates to novel catalyst systems comprising at least one ligand of the following formula

and at least one salt, a complex or an organometallic compound of a metal of the group (Mn, Fe, Co, Ni, Cu, Rh, Pd, Ir, Pt), preferably palladium or nickel. The symbols R _1-6 , X _1-10 , Y _{1 + 2} and Q _1-4 have the abovementioned meaning.

The Metal can be present in any oxidation state. It becomes according to the invention in cross-coupling reactions relative to the reactant (I) in Amounts from 0.001 mol% to 100 mol%, preferably between 0.01 and 10 mol%, more preferably between 0.01 and 1 mol% used.

Of the Catalyst can be added in finished form or in form, e.g. from a pre-catalyst by reduction or hydrolysis or from a metal salt and added Ligands by complex formation.

The Inventive catalyst system is, as will be clarified below, for example, for the following Cross-coupling reactions can be used:

• A) A process for the preparation of mixed Aryl and heteroarylamines and aryl- or heteroaryl-substituted Alkyl / aryl ethers (III) by cross-coupling of primary or secondary Alkyl or arylamines, alcohols or phenols (II) with aryl or Heteroaryl halides or sulfonates (I). When using the catalyst system according to the invention can achieved high yields even with low catalyst loadings (Equation 1), which has the following advantages: • Very high Catalyst activities, since the ligand is present in the reaction mixture as an anion and special has electronic effects. • Easy separation of the ligand as well as metal from the product by aqueous extraction. • The reaction can also be used in protic solvents such as. substituted alcohols are carried out. • The structure the ligand is dependent of the chosen body variable and can be adapted to different needs. • Dependent on selected Ligands can be the bite angle and distance of the two phosphine groups be varied to optimize the effectiveness of the catalyst. • Due high activity the catalyst systems can inexpensive Bases (alkali hydroxides, carbonates) can be used.

GLEICHUNG 1

EQUATION 1

Hal is chlorine, bromine or iodine or sulfonates such as trifluoromethanesulfonate (triflate), Nonafluortrimethylmethansulfonat (nonaflate), methanesulfonate, benzenesulfonate, para-toluenesulfonate or methoxy. X _1-5 independently of one another denote carbon or the group X _i R _i represents nitrogen or in each case two adjacent X _i R _i linked via a formal double bond together represent O (furans), S (thiophenes), NH or NR _i ( pyrroles).

preferred Compounds of the formula (I) which are combined with the catalyst system according to the invention can be implemented by this method are e.g. Benzenes, pyridines, Pyrimidines, pyrazines, pyridazines, furans, thiophenes, pyrroles, arbitrary N-substituted pyrroles or naphthalenes, quinolines, indoles, benzofurans, etc.

The radicals R _1-5 in Equation 1 are substituents from the group {hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 20 C atoms, in which optionally one or more hydrogen atoms by fluorine or chlorine or Bromine, eg CF ₃ , substituted cyclic or acyclic alkyl groups, hydroxy, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, pentafluorosulfuryl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, thio, alkylthio, arylthio, diarylphosphino, Dialkylphosphino, alkylarylphosphino, optionally substituted aminocarbonyl, CO ₂ ^- , alkyl or aryloxycarbonyl, hydroxyalkyl, alkoxyalkyl, fluorine or chlorine, nitro, cyano, aryl or alkylsulfone, aryl or alkylsulfonyl}, or in each case two adjacent radicals R _{1- 5} together correspond to an aromatic, heteroaromatic or aliphatic fused ring.

For Z = O, R 'may be the same or different radicals selected from the group consisting of: hydrogen, methyl, linear, branched C ₁ -C ₂₀ alkyl or cyclic alkyl, substituted or unsubstituted phenyl.

For Z = NR ", R 'and R" independently of one another may represent identical or different radicals from the group {hydrogen, methyl, linear, branched C ₁ -C ₂₀ -alkyl or cyclic alkyl, substituted or unsubstituted phenyl} or together Ring and from the group {optionally substituted alkylene, branched alkylene, cyclic alkylene, substituted azaalkylene, substituted oxaalkylene, substituted phosphaalkylene or optionally substituted Sulfaalkylen} come.

• B) Weiterhin können die erfindungsgemäßen Katalysatorsysteme in Verfahren zur Knüpfung von C-C-Bindungen durch Umsetzung von Aryl- oder Heteroarylhalogeniden und -sulfonaten (I) mit organischen Verbindungen des Bors, Magnesiums, Zinks und Zinns sowie des Siliciums (IV) eingesetzt werden. Im Falle des Einsatzes von Organoborverbindungen ist der Zusatz einer Br⌀nsted-Base in einem Lösungsmittel oder Lösungsmittelgemisch sinnvoll. Auch hier können durch Verwendung der erfindungsgemäßen Katalysatorsysteme mit geringen Katalysatorbeladungen hohe Ausbeuten erzielt werden (Gleichung 2). Im Unterschied zum Verfahren A) bietet dieses Verfahren zusätzlich die Möglichkeit, in wässrigen Lösungsmittelsystemen zu arbeiten.

Typical examples of the compound II in Equation 1 are thus methyl, ethyl, 1-methylethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, butyl and pentylamine, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexylamine, phenyl, benzylamine.

• B) Furthermore, the catalyst systems of the invention can be used in processes for the formation of C-C bonds by reacting aryl or heteroaryl halides and sulfonates (I) with organic compounds of boron, magnesium, zinc and tin and of silicon (IV). In the case of the use of organoboron compounds, the addition of a Brønsted base in a solvent or solvent mixture makes sense. Again, high yields can be achieved by using the catalyst systems of the invention with low catalyst loadings (Equation 2). In contrast to method A), this method additionally offers the possibility of working in aqueous solvent systems.

GLEICHUNG 2

EQUATION 2

Hal and X ₁ -X ₅ and R ₁ -R _{5 have} the meanings described under A).

M stands for Boron, magnesium, zinc, silicon or tin. For M = boron, (n + m) = 3 or at Presence of a counter cation (n + m) = 4 (borates), for M = magnesium or zinc is (n + m) = 2 or in the presence of a counter cation (n + m) = 3 (Magnesates, zincates), for M = tin or silicon (n + m) = 4 (stannanes, silanes, siloxanes).

R 'may each represent one of a total of n identical or different radicals from the group {methyl, linear, branched or cyclic substituted or unsubstituted C ₁ -C ₂₀ -alkyl, vinyl or alkynyl, substituted or unsubstituted aryl or heteroaryl}.

R '' can, for M = boron, each represent one of a total of m identical or different radicals from the group {methyl, linear branched C ₁ -C ₂₀ -alkyl or cyclic substituted or unsubstituted alkyl, vinyl or alkynyl; Hydroxy, linear, branched or cyclic substituted or unsubstituted C ₁ -C ₂₀ alkoxy and dialkylamino} stand, wherein two or more of these R '' may be linked to each other and can form one or more rings; In addition, R "may represent an O-linked radical R '(boronic anhydrides).

R '' may represent, for M = tin, in each case one of a total of m identical or different radicals from the group {methyl, linear branched C ₁ -C ₂₀ -alkyl or cyclic substituted or unsubstituted alkyl, vinyl or alkynyl}.

R '' for M = silicon for each one of a total of m identical or different radicals from the group {methyl, methoxy, linear, branched C ₁ -C ₂₀ alkyl or alkoxy, cyclic substituted or unsubstituted alkyl, alkoxy, vinyl or Alkynyl}.

R '' can be for M = magnesium and M = zinc for one each from a total of m same or different residues of the group {Fluorine, chlorine, bromine, iodine} stand.

• C) In einer weiteren Ausführungsform kann das erfindungsgemäße Katalysatorsystem zur Knüpfung von C-C-Bindungen durch Umsetzung von Aryl- oder Heteroarylhalogeniden und -sulfonaten (I) mit Alkenen (VI) eingesetzt werden (Gleichung 3). Wie bei Verfahren B) besteht auch bei diesem Verfahren vorteilhafterweise zusätzlich die Möglichkeit, in wässrigen Lösungsmittelsystemen zu arbeiten.

Typical examples of compound (IV) are thus aryl or heteroaryl boronic acids and borinic acids (eg 3-fluorophenylboronic acid) and their esters (eg 4-aminophenylboronic acid pinacol ester), tetraarylboranates, vinylboronic acid, butylboronic acid, arylmagnesium halides (eg phenylmagnesium chloride), diarylmagnesium compounds and triarylmagnesates analogous alkyl and aryl zinc compounds, vinyl, alkynyl and aryl trialkyl stannanes and silanes and siloxanes.

• C) In a further embodiment, the catalyst system according to the invention can be used for the formation of C-C bonds by reacting aryl or heteroaryl halides and sulfonates (I) with alkenes (VI) (Equation 3). As in process B), it is also advantageously possible to work in aqueous solvent systems in this process as well.

GLEICHUNG 3

EQUATION 3

Hal and X ₁ -X ₅ and R ₁ -R ₅ may have the meanings described under A).

R ', R' 'and R' '' may be independent of each other for hydrogen or any organic and organoelement substituents, i. Substituents over Heteroatoms are attached, e.g. R'O-, R'S-, R'COO-, etc., where two or more linked together of these radicals be and form one or more rings.

• D) In einer weiteren bevorzugten Ausführungsform können die erfindungsgemäßen Katalysatorsysteme in Kreuzkupplungsverfahren zur Knüpfung von C-C-Bindungen durch Umsetzung von Aryl- oder Heteroarylhalogeniden und -sulfonaten (I) mit terminalen Alkinen (VIII) eingesetzt werden (Gleichung 4). Auch hier werden wieder die vorstehend genannten Vorteile erzielt.

Typical examples of the compound (VI) are thus acrylates, open-chain and cyclic alkenes, styrenes, as well as enamines or enamides.

• D) In a further preferred embodiment, the catalyst systems according to the invention can be used in cross-coupling processes for the formation of C-C bonds by reacting aryl or heteroaryl halides and sulfonates (I) with terminal alkynes (VIII) (Equation 4). Again, the above advantages are achieved again.

GLEICHUNG 4

EQUATION 4

Hal and X ₁ -X ₅ and R ₁ -R ₅ have the meanings described under a).

R 'can be for hydrogen or any organic and elemental organic substituents.

• E) In einer weiteren bevorzugten Ausführungsform können die erfindungsgemäßen Katalysatorsysteme in Kreuzkupplungsverfahren zur Herstellung von 2-Aryl- oder Heteroarylcarbonyl- bzw. -nitrilverbindungen (XI) durch Kreuzkupplung von enolisierbaren Carbonylverbindungen, Nitrilten und ihren Analoga (X) mit substituierten Aryl- oder Heteroarylverbindungen (I) eingesetzt (Gleichungen 5a und 5b), welches sich ebenfalls durch vorstehend genannten Vorteile auszeichnet.

Typical examples of the compound (VIII) are thus acetylene, aliphatic alkynes, arylalkynes and alkynyl ethers.

• E) In a further preferred embodiment, the catalyst systems according to the invention can be used in cross-coupling processes for the preparation of 2-aryl- or heteroarylcarbonyl- or -nitrile compounds (XI) by cross-coupling enolizable carbonyl compounds, nitriles and their analogues (X) with substituted aryl or heteroaryl compounds (X). I) used (equations 5a and 5b), which is also characterized by the advantages mentioned above.

GLEICHUNG 5a

EQUATION 5a

GLEICHUNG 5b

EQUATION 5b

Hal and X ₁ -X ₅ and R ₁ -R ₅ have the meanings described under A).

Z (Equation 5a) stands for O, S, NR '' ', NOR' '' (protected oxime), NNR '' 'R' '' '(double protected Hydrazone) (Equation 5a) or with W together for N alone (Equation 5b).

For Z = O or S, R ', R''may be identical or different radicals from the group {hydrogen, methyl, linear, branched C ₁ -C ₂₀ alkyl or cyclic, optionally substituted alkyl, substituted or unsubstituted aryl or heteroaryl or a non-reactive functional group, eg, carbonyl, carboxyl, N-substituted imine or nitrile, or together form a ring.

R ', R "can independently of one another represent identical or different radicals from the group {hydrogen, methyl, linear, branched C ₁ -C ₂₀ -alkyl or cyclic, optionally substituted alkyl, substituted or unsubstituted aryl or heteroaryl or one not on Reaction participating functional group, eg

carbonyl, Carboxyl, N-substituted imine or nitrile} are or are together or form a ring with W, R '' 'or R' '' '.

For Z = NR ''',NOR''', NNR '''R'''',R''' and R '''' can independently of one another represent identical or different radicals from the group {methyl, linear, branched C C ₁ -C ₂₀ -alkyl or cyclic, optionally substituted alkyl, substituted or unsubstituted aryl or heteroaryl or a non-participating in the reaction functional group, for example carbonyl, carboxyl, N-substituted imine or nitrite} or together or with W or R 'or R''form a ring.

W is a radical from the group {hydrogen, methyl, linear, branched C ₁ -C ₂₀ -alkyl or cyclic, optionally substituted alkyl, substituted or unsubstituted aryl or heteroaryl, optionally substituted alkoxy, aryloxy, heteraryloxy, optionally substituted alkylthio, Arylthio, heteroarylthio, optionally substituted dialkylamino, di (hetero) arylamino, alkyl (hetero) arylamino} and can form a ring with R ', R'',R''' or R '''' (equation 5a).

Z and W can together for a nitrile nitrogen (Equation 5b).

• F) In einer weiteren bevorzugten Ausführungsform können die erfindungsgemäßen Katalysatorsysteme in Verfahren zur Herstellung von Aryl- oder Heteroarylnitrilen (XIII) durch Kreuzkupplung von Cyaniden (XII) mit substituierten Aryl- oder Heteroarylverbindungen (I) eingesetzt werden (Gleichung 6), welches sich ebenfalls durch die vorstehend genannten Vorteile auszeichnet.

Typical examples of the compounds (Xa) and (Xb) in equations 5a + b are thus enolizable ketones, aldehydes, N-substituted imines, thioketones, carboxylic esters, thiocarboxylic esters and nitriles.

• F) In a further preferred embodiment, the catalyst systems of the invention can be used in processes for the preparation of aryl or heteroaryl nitriles (XIII) by cross-coupling of cyanides (XII) with substituted aryl or heteroaryl compounds (I) (Equation 6), which is also characterized by the advantages mentioned above are distinguished.

GLEICHUNG 6

EQUATION 6

Hal and X ₁ -X ₅ and R ₁ -R _{5 have} the meanings described under A).

MCN stands for NaCN, KCN, Zn (CN) ₂ , K ₃ [Fe (CN) ₆ ], K ₄ [Fe (CN) ₆ ], HCN or a cyanohydrin.

Of the Addition of Bronsted bases to the reaction mixture is in all of the above described method A) to F) - except in case B) in use of magnesium, zinc and tin compounds - necessary to acceptable To achieve reaction rates. As bases are well suited Hydroxides, carbonates and fluorides of alkali and alkaline earth metals, carbonates, bicarbonates, Amides and phosphates of alkali metals and their mixtures and aliphatic Amines and other organic nitrogen bases such as pyridines and DBU. Especially suitable for the applications described under A) and E) are the bases of Group {potassium tert-butylate, sodium tert-butylate, cesium-tert-butylate, lithium tert-butylate}; especially suitable for the remaining Applications are the bases of the group {triethylamine, sodium carbonate, Potassium carbonate, cesium carbonate, Potassium phosphate, cesium fluoride, Potassium fluoride, barium hydroxide}. It is usually at least the Amount of base used, the amount of substance to be coupled Nucleophiles, usually 1.0 to 6 equivalents, preferably 1.2 to 3 equivalents used at base based on the nucleophile to be coupled.

All reactions A) to F) described above are in a suitable Solvent or a single- or multi-phase solvent mixture carried out, that a sufficient dissolving power for all involved Reactants has. Well suited are open-chain and cyclic ethers and diethers, oligo- and polyethers as well as substituted simple or multiple alcohols and optionally substituted aromatics, as well as polar aprotic solvents. Particular preference is given to mixtures of a plurality of solvents of the group {diglyme, substituted glymes, 1,4-dioxane, isopropanol, tert-butanol, 2,2-dimethyl-1-propanol, Toluene, xylene, ethylene glycol, tetrahydrofuran, 2-methyltetrahydrofuran, Methanol, ethanol, propanol, isopropanol, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, acetonitrile, propionitrile} used. In case of Coupling of organoboron compounds in application B) is also water a preferred solvent.

The Reaction can be used at temperatures between -30 ° C and the boiling point of the solvent performed at the pressure used become. To achieve a faster response, the implementation is at increased Temperatures in the range of -20 up to 240 ° C prefers. Particularly preferred is the temperature range from 0 to 150 ° C.

All particularly preferred is the temperature range of 20 to 130 ° C for the applications A), D), E), F), from -20 up to 70 ° C when using magnesium and zinc compounds in application B), from 20 to 130 ° C at Use of boron and tin compounds in application B) and of 50 up to 180 ° C for the Application C).

The Concentration of the reactants can be varied within wide limits. Appropriately, will the reaction in as much as possible high concentration, where the solubilities the reactants and reagents in the respective reaction medium must be considered. The reaction is preferably in the range between 0.05 and 5 mol / l based on the reactant present in the deficit.

nucleophilic Reactant (II), (IV), (VI), (VII) or (X) and electrophilic Reactant (I) can in molar ratios from 10: 1 to 1:10 are used, ratios are preferred from 3: 1 to 1: 3 and more preferred are ratios from 1.2: 1 to 1: 1.2.

In one of the preferred embodiments, all materials are initially charged and the mixture is heated with stirring to the reaction temperature. In a further preferred embodiment, which is particularly for large scale use, the nucleophile and optionally other reactants are dosed during the reaction to the reaction mixture.

The Work-up usually takes place with a mixture of aromatic hydrocarbons and water with removal of the aqueous Phase containing the inorganic constituents as well as ligand and transition metal with the product remaining in the organic phase, if non-existent acidic functional groups to a different one Lead phase behavior. If necessary, you can ionic liquids be used for the separation of the polar constituents. The Product is preferred by precipitation or distillation from the organic phase, e.g. by Concentrate or by adding precipitants. Often is an extra Cleaning e.g. by recrystallization or chromatography unnecessary. The isolated yields are usually in the range of 70 to 100%, preferably in the range> 75 % to 100%, in particular> 80 % until 100 %.

• a) gemischte Aryl- und Heteroarylamine sowie aryl- bzw. heteroarylsubstituierte Alkyl-/Arylether ausgehend von den entsprechenden primären oder sekundären Alkyl- bzw. Arylaminen, Alkoholen bzw. Phenolen oder ihren Derivaten und den entsprechenden Aryl- oder Heteroarylhalogeniden oder -sulfonaten herzustellen;
• b) unsymmetrische Biaryle, Heterobiaryle und analoge Kupplungsprodukte ausgehend von den entsprechenden Aryl- bzw. Heteroarylhalogeniden und -sulfonaten, insbesondere den unreaktiven Chloriden, und den entsprechenden Boryderivaten, insbesondere Boronsäuren, Magnesium-, Zink- und Zinnorganylen herzustellen;
• c) Aryl- und Heteroarylvinylverbindungen ausgehend von den entsprechenden Aryl- oder Heteroarylhalogeniden oder -sulfonaten und den entsprechenden Alkenen herzustellen;
• d) Aryl- und Heteroarylalkine ausgehend von den entsprechenden Aryl- oder Heteroarylhalogeniden oder -sulfonaten und den entsprechenden terminalen Alkinen herzustellen,
• e) um in 2-Position arylierte bzw. heteroarylierte Carbonylverbindungen, ihre Derivate und Analoga sowie Nitrile ausgehend von den entsprechenden Carbonylverbindungen bzw. ihren Derivaten und Nitrilen und den entsprechenden Aryl- oder Heteroarylhalogeniden oder -sulfonaten und
• f) Aryl- und Heteroarylnitrile ausgehend von den entsprechenden Aryl- oder Heteroarylhalogeniden und -sulfonaten herzustellen.

The inventive method opens up a very economical method, especially in the aqueous workup to

• a) produce mixed aryl and heteroarylamines and aryl or heteroaryl-substituted alkyl / aryl ethers starting from the corresponding primary or secondary alkyl or arylamines, alcohols or phenols or their derivatives and the corresponding aryl or heteroaryl halides or sulfonates;
• b) unsymmetrical biaryls, heterobiaryls and analogous coupling products starting from the corresponding aryl or heteroaryl halides and sulfonates, in particular the unreactive chlorides, and the corresponding boryderivatives, in particular boronic acids, magnesium, zinc and tin organyls;
• c) preparing aryl and heteroaryl vinyl compounds starting from the corresponding aryl or heteroaryl halides or sulfonates and the corresponding alkenes;
• d) preparing aryl and heteroaryl alkynes starting from the corresponding aryl or heteroaryl halides or sulfonates and the corresponding terminal alkynes,
• e) arylated in 2-position or heteroarylated carbonyl compounds, their derivatives and analogs and nitriles starting from the corresponding carbonyl compounds or their derivatives and nitriles and the corresponding aryl or heteroaryl halides or sulfonates and
• f) producing aryl and heteroaryl nitriles starting from the corresponding aryl or heteroaryl halides and sulfonates.

The Products are obtained in high purity and yield, so on consuming Cleaning procedures such as e.g. Chromatography mostly omitted can be.

In addition causes the sulfonation of the ligand in most cases a significant acceleration to the reaction the use of the unsulfonated ligand.

By Variation of the bridging Leaves groups in the ligand to modify the bite angle in order to optimize the effectiveness of the Ligands for the wished Purpose to achieve.

The inventive method should be illustrated by the following examples, without the invention to limit it to:

Example 1: 4,5-Bis-diphenylphosphino-9,9-dimethyl-9H-xanthene-2,7-bis (sodium sulfonate) (L1)

This Ligand was prepared according to a protocol of van Leeuwen et al., Adv. Synth. Catal. 2002, 293.

Example 2: Coupling of Chlorobenzene with 2,3-dimethylaniline to give N- (2,3-dimethylphenyl) -aniline under L1-Pd catalysis

113 mg (1 mmol) chlorobenzene, 121 mg (1 mmol) 2,3-dimethylaniline, 192 mg (2 mmol) sodium tert-butoxide, 4.4 mg palladium (II) acetate (2 Mol%) and 16 mg L1 (2 mol%) were dissolved in 6 ml of degassed, anhydrous diglyme for 19 h to 100 ° C heated. After cooling the reaction mixture was added to 10 ml of water and the mixture extracted with 10 ml of toluene. The toluene phase was removed of diglyme residues washed with 5 ml of water and rotary evaporator concentrated. After drying in vacuo, 188 mg (0.95 mmol, 95%) of the product.

Example 3: Coupling of Chlorobenzene with 2,3-dimethylaniline to give N- (2,3-dimethylphenyl) -aniline under Xantphos-Pd catalysis

Execution like Example 10, instead of L1, was commercially available for comparison Ligand Xantphos (4,5-bis-diphenylphosphino-9,9-dimethyl-9H-xanthene) used, which corresponds to the unsulfonated L1. The product was by flash chromatography (mobile phase cyclohexane / ethyl acetate 10: 1) cleaned. Only 162 mg (0.82 mmol, 82%) of the product were obtained.

Example 4: Coupling of 4-chloroanisole with 2,3-dimethylaniline to give (2,3-dimethylphenyl) - (4-methoxyphenyl) amine L1 Pd catalysis

143 mg (1 mmol) 4-chloroanisole, 121 mg (1 mmol) 2,3-dimethylaniline, 192 mg (2 mmol) sodium tert -butoxide, 4.4 mg palladium (II) acetate (2 Mol%) and 16 mg L1 (2 mol%) were dissolved in 6 ml degassed, anhydrous Diglyme for 30 h at 100 ° C heated. After cooling the reaction mixture was added to 10 ml of water and the mixture extracted with 10 ml of toluene. The toluene phase was removed of diglyme residues washed with 5 ml of water and rotary evaporator concentrated. After drying in vacuo, 166 mg (0.73 mmol, 73%) of the product.

Example 5: Coupling of 2-Bromo-4-fluorotoluene with 2,3-dimethylaniline to 5-fluoro-2,2 ', 3'-trimethyl-diphenylamine under L1-Pd catalysis

189 mg (1 mmol) 2-bromo-4-fluorotoluene, 121 mg (1 mmol) 2,3-dimethylaniline, 192 mg (2 mmol) of sodium tert-butoxide, 4.4 mg of palladium (II) acetate (2 mol%) and 16 mg of L1 (2 mol%) were dissolved in 6 ml of degassed, anhydrous Diglyme for 15 h at 120 ° C heated. After cooling the reaction mixture was added to 10 ml of water and the mixture extracted with 10 ml of toluene. The toluene phase was removed of diglyme residues washed with 5 ml of water and rotary evaporator concentrated. After drying in vacuo, 225 mg (0.98 mmol, 98%) of the product.

Example 6: Coupling of 1-bromonaphthalene with 2,3-dimethylaniline to give (2,3-dimethylphenyl) -naphtalin-1-ylamine L1 Pd catalysis

Of the Trial was performed as previously described, but instead of 2-bromo-4-fluorotoluene used 207 mg of 1-bromonaphthalene (1 mmol). The yield was 245 mg (0.99 mmol, 99%).

Example 7: Coupling of 4-chloroanisole with 4-tolylboronic acid to 4-methoxy-4'-methylbiphenyl below L1 Pd catalysis

143 mg 4-chloroanisole (1 mmol), 136 mg 4-tolylboronic acid, 0.18 mg palladium chloride (0.1 mol%), 0.78 mg of L1 (0.1 mol%) and 74 mg of sodium carbonate (0.8 mmol) were suspended in 1 ml of ethylene glycol and 0.2 ml of water. It was heated for 3 h at 110 ° C, diluted the reaction mixture with 2 ml of toluene, separated the aqueous phase extracted again with 2 ml of toluene and concentrated the combined Toluene phases on a rotary evaporator. 190 mg (0.96 mmol, 96%) of a colorless solid.

Example 8: Coupling of 2-Chlorobenzonitrile with 4-tolylboronic acid to 2-cyano-4'-methylbiphenyl under L1-Pd catalysis

138 mg 2-chlorobenzonitrile (1 mmol), 136 mg 4-tolylboronic acid, 0.18 mg palladium chloride (0.1 mol%), 0.78 mg L1 (0.1 mol%) and 74 mg Sodium carbonate (0.8 mmol) was dissolved in 1 ml of ethylene glycol and 0.2 ml of water suspended. The mixture was heated at 110 ° C. for 0.5 h, and the mixture was diluted Reaction mixture with 2 ml of toluene, the aqueous phase separated, extracted again with 2 ml of toluene and concentrated the combined toluene on a rotary evaporator. 191 mg (0.99 mmol, 99%) were obtained. a colorless solid.

Example 9: Coupling of 2-chlorobenzonitrile with tributylphenylstannane to 2-chlorobiphenyl below L1 Pd catalysis

138 mg of 2-chlorobenzonitrile (1 mmol), 0.18 mg of palladium chloride (0.1 mol%), 0.78 mg of L1 (0.1 mol%) and 551 mg tributylphenylstannane (1.5 mmol) were dissolved in 6 ml of dry tetrahydrofuran and at 60 ° for 12 h C stirred. After cooling, the mixture was treated with 305 mg DBU, stirred for 5 min and then extracted twice with 5 ml of water. The organic phase was concentrated and freed from tin-containing residues by flash chromatography (ethyl acetate / cyclohexane 1: 9). 168 mg (0.89 mmol, 89%) of a yellowish solid.

Example 10: Coupling of 2-tolylmagnesium chloride with 4-chlorobenzotrifluoride under L1-Ni catalysis

271 mg 4-chlorobenzotrifluoride (1 .5 mmol), 0.26 mg anhydrous nickel (II) chloride (0.02 mmol) and 1.57 mg of L1 (0.02 mmol) were dissolved in 2 ml of tetrahydrofuran submitted and for 30 min at 60 ° C. heated. About 2 h was at this temperature 1 ml of a 1M solution of 2-tolylmagnesium chloride added in tetrahydrofuran. It was left for 30 min at this temperature stirred, cooled to room temperature, added 2 ml of 2M hydrochloric acid, the phases separated, washed with 1 ml of water and the organic phase was concentrated on a rotary evaporator one. This gave 215 mg (0.91 mmol, 91%) of a colorless oil.

Example 11: Coupling of 4-chloroanisole with diphenylzinc to 4-methoxybiphenyl under L1-Pd catalysis

143 mg 4-chloroanisole (1 mmol), 0.18 mg palladium chloride (0.1 mol%), 0.78 mg of L1 (0.1 mol%) and 220 mg of diphenylzinc (1 mmol) were dissolved in 5 ml of tetrahydrofuran for 15 h at 60 ° C heated. After cooling to Room temperature, 3 ml of 2M hydrochloric acid were added, the phases were separated, washed with 1 ml of water and the organic phase on a rotary evaporator concentrated. 171 mg (0.93 mmol, 93%) of a colorless solid were obtained.

Example 12: Coupling of 4-chlorobenzophenone with butyl acrylate to 3- (4-benzoyl-phenyl) -acrylic acid butyl ester under L1 Pd catalysis

217 mg 4-chlorobenzophenone (1 mmol), 192 mg butyl acrylate (1 .5 mmol), 0.18 mg palladium chloride (0.1 mol%) and 0.78 mg L1 (0.1 mol%) were dissolved in a mixture of 4.5 ml of N, N-dimethylacetamide and 0.5 ml Triethylamine in a closed Schlenk tube for 4 h Heated to 135 ° C. After cooling The reaction mixture was diluted with 5 ml of water and washed twice with 5 ml Extracted toluene. The combined toluene extracts were washed with 3 ml of water and concentrated on a rotary evaporator. This gave 268 mg (0.87 mmol, 87%) of a slightly yellowish oil.

Example 13: Coupling of 4-chlorobenzyl alcohol with styrene to 4-hydroxymethylstilbene below L1 Pd catalysis

143 mg 4-chlorobenzophenone (1 mmol), 156 mg styrene (1.5 mmol), 0.18 mg Palladium chloride (0.1 mol%) and 0.78 mg of L1 (0.1 mol%) were dissolved in a mixture of 4.5 ml of N, N-dimethylacetamide and 0.5 ml of triethylamine 18 h in a closed Schlenk vessel Heated to 135 ° C. After cooling The reaction mixture was diluted with 5 ml of water and washed twice with 5 ml Extracted toluene. The combined toluene extracts were washed with 3 ml of water and concentrated on a rotary evaporator. 189 mg (0.90 mmol, 90%) of a yellowish oil.

Example 14: Coupling of 4-chloroacetophenone with phenylacetylene to give 1- (4-phenylethynylphenyl) -ethanone catalyzed by L1-Pd

155 mg 4-chloroacetophenone (1 mmol), 153 mg phenylacetylene (1.5 mmol), 3.5 mg palladium (II) chloride (2 mol%), 16 mg L1 (2 mol%), 190 mg of copper (I) iodide (1 mmol) and 212 mg of sodium carbonate (2 mmol) in 5 ml of degassed toluene for 6 h at 100 ° C heated. After cooling to room temperature was extracted twice with 5 ml of water and the organic phase is concentrated on a rotary evaporator. One received 216 mg (0.98 mmol, 98%) of a colorless oil.

Example 15: Coupling of 4-chloroanisole with phenylacetylene to 1-methoxy-4-phenylethynylbenzene catalyzed by L1-Pd

143 mg 4-chloroanisole (1 mmol), 153 mg phenylacetylene (1.5 mmol), 3.5 mg palladium (II) chloride (2 mol%), 16 mg L1 (2 mol%), 190 mg copper (I) iodide (1 mmol) and 212 mg of sodium carbonate (2 mmol) were degassed in 5 ml Toluene for 18 hours at 100 ° C heated. After cooling to room temperature was extracted twice with 5 ml of water and the organic phase is concentrated on a rotary evaporator. One received 165 mg (0.79 mmol, 79%) of a colorless oil.

Example 16: Coupling of 4-bromobenzonitrile with acetophenone to give 4- (2-oxo-2-phenylethyl) benzonitrile under L1-Pd catalysis

182 mg of 4-bromobenzonitrile (1 mmol) and 120 mg of acetophenone (1 mmol) were added under protective gas in 5 Dissolved N, N-dimethylformamide and treated with 192 mg of sodium tert-butoxide (2 mmol). The mixture was stirred for 15 minutes and then 4.4 mg of palladium (II) acetate (2 mol%) and 16 mg of L1 (2 mol%) were added and heated to 80 ° C for 8 h.

to Work-up was added 5 ml of water and 10 ml of toluene, shaken, the drained lower water phase and to remove residual dimethylformamide washed again with 5 ml of water. The solvent was on a rotary evaporator removed in a vacuum. 208 mg of the product (0.94 mmol, 94%).

Example 17: Coupling of 4-bromobenzonitrile with cyclohexanone to 4- (2-oxocyclohexyl) benzonitrile

182 mg of 4-bromobenzonitrile (1 mmol) and 98 mg of cyclohexanone (1 mmol) dissolved under inert gas in 5 ml of N, N-dimethylformamide and with 192 mg of sodium tert-butoxide (2 mmol). One left 15 stir and min then gave 4.4 mg of palladium (II) acetate (2 mol%) and 16 mg of L1 (2 mol%) to and heated for 13 h at 80 ° C.

to Work-up was added 5 ml of water and 10 ml of toluene, shaken, the drained lower water phase and to remove residual dimethylformamide washed again with 5 ml of water. The solvent was on a rotary evaporator removed in a vacuum. After flash chromatography (cyclohexane / ethyl acetate 10: 1) 142 mg of the product (0.71 mmol, 71%).

Example 18: Coupling of 4-chlorobromobenzene with malodinitrile to 1-chloro-4-dicyanomethylbenzene

191.5 mg of 4-chlorobromobenzene (1 mmol) and 66 mg of malononitrile (1 mmol) under protective gas dissolved in 5 ml of N, N-dimethylformamide, with 343 mg of barium hydroxide (2 mmol) and stirred for 1 h. Then, 4.4 mg of palladium (II) acetate (2 mol%) and 16 mg of L1 (2 Mol%) was added and for 18 hours at 80 ° C heated.

to Work-up was added 5 ml of water and 10 ml of toluene, shaken, the lowered lower water phase and again to remove residual dimethylformamide washed with 5 ml of water. After removal of the toluene on a rotary evaporator 156 mg (0.89 mmol, 89%) of the product were obtained.

Example 19: Coupling of 4-chloroacetophenone with zinc cyanide to 4-cyanoacetophenone below L1 Pd catalysis

155 mg 4-chloroacetophenone (1 mmol), 70 mg zinc cyanide (0.6 mmol), 4.4 mg of palladium (II) acetate (2 mol%) and 16 mg of L1 (2 mol%) in 5 ml of degassed N, N-dimethylformamide for 12 h at 80 ° C heated. To Cooling At room temperature, the reaction mixture was diluted with 5 ml of water and extracted twice with 5 ml of toluene. The combined toluene extracts were washed again with 5 ml of water and then on a rotary evaporator concentrated. This gave 139 mg (0.96 mmol, 96%) of a colorless Solid.

Example 20: Coupling of 4-chloroanisole with zinc cyanide to 4-methoxybenzonitrile under L1-Pd catalysis

143 mg 4-chloroanisole (1 mmol), 70 mg zinc cyanide (0.6 mmol), 4.4 mg palladium (II) acetate (2 mol%) and 16 mg of L1 (2 mol%) were dissolved in 5 ml of degassed N, N-dimethylformamide for 12 h at 80 ° C heated. After cooling At room temperature, the reaction mixture was diluted with 5 ml of water and extracted twice with 5 ml of toluene. The combined toluene extracts were washed again with 5 ml of water and then on a rotary evaporator concentrated. 117 mg (0.88 mmol, 88%) of a colorless product were obtained Solid.

Claims (17)

Sulfonated phosphine ligands of the structure

wherein X is _4-7 for carbon, nitrogen or phosphorus, X _1-3 and X _8-10 independently of one another either for carbon, or the group X _i R _i with i = 2, 3, 4 or 5 for nitrogen or phosphorus or respectively two neighbors X _i R _i linked via a formal double bond together represent O, S, NH or NR _i ; the radicals R _1-6 are substituents from the group {hydrogen, methyl, primary, secondary or tertiary, cyclic or acyclic alkyl radicals having 2 to 20 C atoms, in which optionally one or more hydrogen atoms are replaced by fluorine or chlorine or bromine , Hydroxy, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, pentafluorosulfuranyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, thio, alkylthio, arylthio, diarylphosphino, dialkylphosphino, alkylarylphosphino, optionally substituted aminocarbonyl, CO ₂ , alkyl- or aryloxycarbonyl, hydroxyalkyl, alkoxyalkyl, nitro, cyano, aryl or alkylsulfone, aryl or alkylsulfonyl}, or in each case two adjacent radicals R _1-5 together represent an aromatic, heteroaromatic or aliphatic fused ring, with the proviso that at least one R _1-3 and R _{4-6 of} a sulfonate group corresponds to Y ₁ and Y ₂ independently represents a the same or different bridging, bidentate or trivalent structural elements from the group {oxygen, sulfur, substituted nitrogen or phosphorus, optionally substituted C _1-3 -alkylene, -vinylene, -alkylidene or silaalkylene, optionally substituted arylene or heteroarylene, carboxylate, thiocarboxylate , N-substituted carboxamide or imide, optionally substituted silane, single bond}, wherein the middle ring may have aliphatic, heteroaliphatic, aromatic or heteroaromatic character; with the proviso that when Y _{1 is} -C (CH ₃ ) ₂ - and R ₂ = R ₅ = sulfonate, at least one further of R _1-3 and R _{4-6 is} not hydrogen or at least one of the groups Q _{1-4 is} not phenyl, Q _1-4 independently of one another are identical or different radicals from the group {hydrogen, methyl, linear, branched or cyclic alkyl, optionally substituted, aryl, heteroaryl, optionally substituted} or Q ₁ and Q ₂ or Q ₃ and Q ₄ together form a ring and represent a bridging structural element from the group {optionally substituted alkylene, branched alkylene, cyclic alkylene, optionally substituted arylene or heteroarylene} or independently of one another for one or two polycyclic radicals, such as norbornyl or adamantyl ; Q _1-4 may carry one or more sulfonic acid or sulfonate groups. Ligands according to claim 1, characterized in that Y _{1 represents} an optionally substituted alkylene group, alkylidene, vinylidene or vinylene group and Y ₂ = O and in each case one of the radicals R ₁ -R ₃ and R ₄ -R ₆ corresponds to a sulfonate group. Ligands according to claim 1, characterized in that Y _{1 represents} an optionally substituted silylene or silaalkylene group and Y ₂ = O and in each case one of the radicals R ₁ -R ₃ and R ₄ -R ₆ corresponds to a sulfonate group. Ligands according to claim 1, characterized in that Y _{1 represents} a sulfur atom or an optionally substituted thiaalkylene group and Y ₂ = O and in each case one of the radicals R ₁ -R ₃ and R ₄ -R ₆ corresponds to a sulfonate group. Ligands according to claim 1, characterized in that Y ₁ denotes a single bond and Y ₂ = O and in each case one of the radicals R ₁ -R ₃ and R ₄ -R ₆ corresponds to a sulfonate group. Ligands according to claim 1, characterized in that Y _{1 represents} a substituted nitrogen atom or an N-substituted azaalkylene group and Y ₂ = O and in each case one of the radicals R ₁ -R ₃ and R ₄ -R ₆ corresponds to a sulfonate group. Ligands according to claims 3-6, characterized in that Y ₁ is sulfur instead of oxygen. Catalyst systems comprising at least one ligand of the following formula

and at least one salt, complex or organometallic compound of a metal of the group {Mn, Fe, Co, Ni, Cu, Rh, Pd, Ir, Pt}, preferably palladium or nickel, and wherein the symbols R _1-6 , X _1-10 , Y _{1 + 2} and Q _1-4 are as defined in Claim 1 have said meaning. Use of a catalyst system according to claim 8 for cross-coupling reactions of aryl and heteroaryl halides and sulfonates with amines, Alcohols and carbon nucleophiles. Process for the cross-coupling of aryl and heteroaryl halides and sulfonates with amines, alcohols and carbon nucleophiles, characterized in that the cross-coupling in the presence of a Ligands according to at least one of the claims 1 to 8, a transition metal of the group {Mn, Fe, Co, Ni, Rh, Pd, Ir, Pt} and a Brønsted base in a solvent or solvent mixture carried out becomes. Method according to claim 10, characterized in that that as a Brønsted base a hydroxide or alkoxide of the alkali or alkaline earth metals or an alkali carbonate or phosphate or mixtures of these compounds be used. Method according to claim 10 or 11, characterized that is 1.0 to 3 equivalents to base based on the aryl or heteroaryl halide or aryl or heteroarylsulfonate can be used. Method according to at least one of claims 10 to 12, characterized in that as the solvent open-chain and cyclic ethers and diethers, oligo- and polyethers as well as substituted ones single or multiple alcohols and optionally substituted Aromatics, N, N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, tertiary Amines, acetonitrile, propionitrile or a mixture of several of these solvent is used. Method according to at least one of claims 10 to 13, characterized in that the reaction at a temperature in the range of -20 up to 240 ° C carried out becomes. Method according to claim 14, characterized in that the reaction is carried out at a temperature in the range of 0 to 150 ° C. Method according to at least one of claims 10 to 15, characterized in that as catalyst or pre-catalyst a salt, a complex or an organometallic compound of a Metal of the group {Fe, Co, Ni, Pd} is used. Method according to at least one of claims 10 to 16, characterized in that the catalyst in relation to Reactants in amounts of 0.001 mol% to 100 mol% is used.